Genetics is now allowing the dissection of the etiology of the frontotemporal dementias and the other tauopathies (progressive supranuclear palsy, Pick's disease, corticobasal degeneration). Mutations in the tau gene are one cause of frontotemporal dementia, but there is an-as-yet unidentified gene on chromosome 3 which leads to a very similar syndrome and there are likely to be other genetic loci involved in this heterologous condition. We seek funds to clone the gene on chromosome 3 involved in this disease and to develop a family resource to allow us to start to characterize other loci involved in these syndromes. The genetic relationship between Pick's disease and frontotemporal dementia is not clear: we seek to elucidate this relationship through the analysis of the tau locus in this disease. A robust association has been reported between an intronic polymorphism in the tau gene and PSP. This leads to the expectation that genetic variability in this gene leads directly to the disease. However, the nature of this genetic variability is not clear. We seek funds to examine the tau gene in PSP and the related disease, CBD, both by sequencing and by genetic analysis. Finally, we will test whether genetic variability in either the tau or synuclein genes contribute to the occurrence of the 'low-tangle' Lewy body variant of Alzheimer's disease.